Combination therapies incorporating hK1 inhibition/silencing PD173955? as adjuvant to imatinib mesylate therapy may be useful for the treatment of GIST. Acknowledgments P Dominek was supported by a studentship of the Pathological Society of Great Britain and Ireland. We are thankful to Dr J Fletcher, Dr S Bauer and J Ketzer for providing cell lines GIST882 and GIST48.
The hepatitis C virus (HCV) is a leading cause of chronic liver disease and increased risk of cirrhosis and hepatocellular carcinoma (51). More than 170 million people are infected with HCV worldwide (42). This enveloped, single-stranded positive-sense RNA virus is a member of the Flaviviridae family. The RNA genome contains a single large open reading frame composed of over 9,000 nucleotides (nt) encoding structural and nonstructural proteins (5).
One of these proteins is an RNA-dependent RNA polymerase encoded by the so-called NS5B region. This error-prone enzyme lacks proofreading activity, which makes it responsible for the great genetic variability of HCV. Sequencing studies of HCV strains have identified 6 genotypes and more than 70 subtypes (43, 45). The HCV genotype is considered to be the major baseline predictor of a sustained virological response (SVR) to antiviral therapy. Patients infected with HCV genotypes 2 and 3 are more sensitive to combination therapy with interferon and ribavirin than are those infected with genotype 1 (8, 11, 21). The available data on HCV genotype 4 suggest that its sensitivity to HCV treatment lies somewhere between those of genotypes 1 and 2/3 (17).
The sensitivity of genotypes 5 and 6 could be similar to that of genotype 2 or 3 (1, 9, 19). The HCV subtype has recently been implicated as a potential predictor of SVR. One study of 597 difficult-to-treat patients found that subtypes 1b, 4a, and 4d were independently associated with SVR (16). The virological response to new anti-HCV agents could also be influenced by the HCV subtype (31, 42). Several methods has been proposed for HCV genotyping (50), including commercially available techniques based on real-time PCR: the HCV genotyping analyte-specific reagent (ASR) assay (Abbott Molecular Inc., Des Plaines, IL) (23), semiautomated sequencing (the TruGene HCV 5��NC genotyping kit; Bayer HealthCare, Berkeley, CA) (10), and automated reverse hybridization (the Inno-LiPA HCV II assay; Innogenetics, Ghent, Belgium) (46, 49).
Most HCV genotyping methods are based on analysis of the 5�� noncoding (NC) region of the HCV genome because the 5�� NC region is regularly amplified for HCV molecular diagnosis and quantification of the viral load. However, this highly conserved region is not suitable for accurately discriminating between subtypes and can lead to genotyping or subtyping errors (2, 3, 15, 39, 43). Hence, AV-951 alternative genomic regions have been proposed for genotyping HCV, including the core fragment (35, 49) and the NS5B region (39).